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Structure of SRSF1 RRM1 bound to RNA reveals an unexpected bimodal mode of interaction and explains its involvement in SMN1 exon7 splicing

Author

Listed:
  • Antoine Cléry

    (Institute of Biochemistry, ETH Zurich
    Biomolecular NMR Spectroscopy Platform, ETH Zurich)

  • Miroslav Krepl

    (Institute of Biophysics of the Czech Academy of Sciences)

  • Cristina K. X. Nguyen

    (Institute of Biochemistry, ETH Zurich)

  • Ahmed Moursy

    (Institute of Biochemistry, ETH Zurich)

  • Hadi Jorjani

    (University of Basel)

  • Maria Katsantoni

    (University of Basel)

  • Michal Okoniewski

    (Scientific IT Services, ETH Zurich)

  • Nitish Mittal

    (University of Basel)

  • Mihaela Zavolan

    (University of Basel)

  • Jiri Sponer

    (Institute of Biophysics of the Czech Academy of Sciences)

  • Frédéric H.-T. Allain

    (Institute of Biochemistry, ETH Zurich)

Abstract

The human prototypical SR protein SRSF1 is an oncoprotein that contains two RRMs and plays a pivotal role in RNA metabolism. We determined the structure of the RRM1 bound to RNA and found that the domain binds preferentially to a CN motif (N is for any nucleotide). Based on this solution structure, we engineered a protein containing a single glutamate to asparagine mutation (E87N), which gains the ability to bind to uridines and thereby activates SMN exon7 inclusion, a strategy that is used to cure spinal muscular atrophy. Finally, we revealed that the flexible inter-RRM linker of SRSF1 allows RRM1 to bind RNA on both sides of RRM2 binding site. Besides revealing an unexpected bimodal mode of interaction of SRSF1 with RNA, which will be of interest to design new therapeutic strategies, this study brings a new perspective on the mode of action of SRSF1 in cells.

Suggested Citation

  • Antoine Cléry & Miroslav Krepl & Cristina K. X. Nguyen & Ahmed Moursy & Hadi Jorjani & Maria Katsantoni & Michal Okoniewski & Nitish Mittal & Mihaela Zavolan & Jiri Sponer & Frédéric H.-T. Allain, 2021. "Structure of SRSF1 RRM1 bound to RNA reveals an unexpected bimodal mode of interaction and explains its involvement in SMN1 exon7 splicing," Nature Communications, Nature, vol. 12(1), pages 1-12, December.
    • Handle: RePEc:nat:natcom:v:12:y:2021:i:1:d:10.1038_s41467-020-20481-w
    DOI: 10.1038/s41467-020-20481-w
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    Cited by:

    1. Xuan Ye & Wen Yang & Soon Yi & Yanan Zhao & Gabriele Varani & Eckhard Jankowsky & Fan Yang, 2023. "Two distinct binding modes provide the RNA-binding protein RbFox with extraordinary sequence specificity," Nature Communications, Nature, vol. 14(1), pages 1-12, December.

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